PROJECT SUMMARY/ABSTRACT - OVERALL The overarching goal of the proposed research is to advance our understanding of age-related hearing loss (presbyacusis). More than 37 million American adults have impaired hearing and this number is rising rapidly due to our growing aging society. Interventions for presbyacusis have relatively limited effectiveness, due in part to our incomplete understanding of the distinct metabolic, sensory, and neural mechanisms underlying hearing and communication difficulties in older adults. Four integrated scientific projects are supported by a human subjects core and will test hypotheses about the pathophysiology and genetic, molecular, and cellular mechanisms underlying presbyacusis, examine their consequences for communication, develop tools that improve the diagnostic specificity of presbyacusis, and provide guidance for individualized interventions. Project 1 identifies genetic variants for presbyacusis, characterizes their associated pathophysiology, defines their effects on hearing loss, and assesses the pathologic consequences of these variants in human temporal bones. Project 2 examines how age-dependent changes in the cochlea's innate immune system contribute to degeneration of the cochlear lateral wall and auditory nerve, leading to metabolic and neural presbyacusis. Project 3 uses unique physiologic metrics shared with Project 2 that differentiate metabolic, sensory, and neural presbyacusis in human subjects. Using these same subjects, Project 4 examines acoustic-level phonetic cue and executive system explanations for why older adults experience speech recognition difficulties. Thus, the four scientific projects are interrelated and complementary across levels of analysis to integrate data from animal models, human subjects, and human tissue for the extensive characterization of the pathophysiology of presbyacusis from the inner ear to cortex. Core A (Administration) provides and supports an administrative structure to integrate all scientific activities of the Clinical Research Center. Core B (Human Subjects) recruits human subjects and coordinates their schedules, and supports collection, storage, and analysis of data, which are shared with other research groups to confirm our findings and extend the impact of our research. Together, the proposed research and comprehensive longitudinal human subject database form a cohesive, translational program that will advance our understanding of human presbyacusis and promote scientific progress through sharing of data and presbyacusis phenotyping tools. The Clinical Research Center is unique because of its 30-year longitudinal study of hearing in older adults, clinical and translational approaches, and a focus on providing strong evidence to enhance hearing health care for the millions of Americans who have reduced quality of life because of poorer hearing and communication abilities. The Center will continue to guide the theoretical and clinical study of audition and precision treatments for presbyacusis.